title: Alleviation of oxidative stress by potent and selective thioredoxin-mimetic peptides.
abstract: One of the major enzymatic cell defenses providing protection from oxidative injury is the TrxR-Trx system. It consists of NADPH and thioredoxin reductase (TrxR), which maintain thioredoxin (Trx) in a reduced state. Perturbing the TrxR-Trx system with the selective TrxR inhibitor auranofin (AuF; 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranosato-S-(triethylphosphine) gold) induces oxidative stress by keeping Trx in its oxidized state. We have prepared a family of tri- and tetra-oligopeptides derived from the canonical CxxC motif of the Trx active site and a modified CxC motif. These Trx-mimetic compounds are N- and C-terminal-blocked peptides that consist of two cysteine residues that flank the two-amino-acid CxxC motif (CB4 and CB6) or the single-amino-acid CxC motif (CB3). Catecholamine (CA) secretion in bovine chromaffin cells, which is a highly redox sensitive process, is abolished by AuF. The Trx-mimetic peptides effectively restore CA secretion, as monitored by amperometry in single cells. They also prevent the AuF-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase. In PC12 cells, the alleviation of AuF-induced ERK1/2-MAPK phosphorylation by Trx-like peptides parallels their effect of restoring CA secretion. CB3, CB4, and CB6 act intracellularly and are significantly more potent than the traditional antioxidants NAC, GSH, DTT, AD4 (NAC-amide), and ascorbic acid. Taken together, the CxxC and CxC peptides represent a new family of potent and selective redox compounds that could serve as potential candidates for prevention and treatment of oxidative-stress-related disorders.
authors.affiliation: The Institute of Life Sciences, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Niv
authors.initials: N
authors.lastname: Bachnoff
authors.forename: Michael
authors.initials: M
authors.lastname: Trus
authors.forename: Daphne
authors.initials: D
authors.lastname: Atlas
mesh_terms: D000818:Animals; D001310:Auranofin / Q000494:pharmacology; D002395:Catecholamines / Q000037:antagonists & inhibitors / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D018716:Molecular Mimicry; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013879:Thioredoxins / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D010455:Peptides; D001310:Auranofin; D013879:Thioredoxins